Synthesis and biological evaluation of potent glycosidase inhibitors: 4-deoxy-4,4-difluoroisofagomine and analogues

Article abstract of DOI:10.1016/j.tet.2009.02.079

A series of 4,4-difluoroisofagomine analogues were synthesized. These compounds were tested for inhibition of eight glycosidases. The 3R,5R isomer 1 is a new and potent inhibitor against β-glucosidase from almonds with K_i value of 1.2 μM. The i

Full text of DOI:10.1016/j.tet.2009.02.079

Tetrahedron 65 (2009) 3717–3727
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journal homepage: www.elsevier.com/locate/tet
Synthesis and biological evaluation of potent glycosidase inhibitors: 4-deoxy-
4,4-difluoroisofagomine and analogues
,
Rui-jie Li a, Mikael Bols b, Cyril Rousseau b, Xin-gang Zhang a, Ruo-wen Wang a, Feng-Ling Qing a
*
a Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Science, 345 Lingling Lu, Shanghai 200032, China
b Department of Chemistry, University of Copenhagen, Universitetsparken 5, Denmark
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of 4,4-difluoroisofagomine analogues were synthesized. These compounds were tested for in-
Received 10 January 2009
Received in revised form 19 February 2009
Accepted 20 February 2009
Available online 5 March 2009
hibition of eight glycosidases. The 3R,5R isomer 1 is a new and potent inhibitor against
from almonds with Ki value of 1.2 M. The influence of the gem-difluoromethylene group (CF2) on
binding to glycosidases is discussed. It is concluded that only non-essential hydroxyl groups can be
b-glucosidase
m
replaced by the gem-difluoro group and that in such a case (
b
-glycosidase) the change in inhibition is,
interestingly, a result of the change in base strength.
Keywords:
Ó 2009 Elsevier Ltd. All rights reserved.
Iminosugar
Glycosidases inhibitors
Fluorinated compounds
1. Introduction
a promising strategy for obtaining stronger and more selective in-
hibitors toward a certain glycosidase of therapeutic interest. In re-
cent years, employing this strategy, tremendous efforts have been
made.7 However, rare reports have described the effect of electron-
withdrawing groups on the iminosugars bioactivities, especially
when electron-withdrawing groups are introduced in the piperi-
dine ring.8 Recently we designed and synthesized gem-4,4-
difluoromethylated nojirimycin analogues, and found that the
strongly electron-withdrawing gem-difluoromethylene group had
an important influence on the inhibition of glycosidase.9 To con-
tinue our research on the fluorinated glycosidase inhibitors, herein,
we first described the synthesis and biological evaluation of 4-
deoxy-4,4-difluoroisofagomine analogues 1–14 (Fig. 2).
Iminosugars and azasugars (polyhydroxypiperidines and pyr-
rolidines), which frequently are analogues of natural products, have
attracted increasing attention for synthetic chemists and bio-
chemists due to their significant biological activities. They often
serve as strong inhibitors of glycosidases and glycotransferases1
and have a tremendous potential as agents to treat a variety of
carbohydrate-mediated diseases, such as diabetes, cancer, AIDS,
hepatitis, Gaucher’s disease, and influenza.2 Among this group of
inhibitors, N-butyl-1-DNJ (Zavesca) and N-hydroxyethyl-DNJ
(Miglitol) have been successfully completed clinical trials for type I
Gaucher disease and lysosomal storage disorder.3 Isofagomine
(Fig. 1), which mimic the transition state of glycoside cleavage in its
protonated form, shows a broad spectrum of strong inhibition
The design of 4-deoxy-4,4-difluoroisofagomine analogues 1–
14 was based on the following considerations: Firstly, isofagomine
and its stereoisomer isogalactofagomine are very potent in-
against glycosidases, especially
b
-glucosidase (sweet almond).4
Noteworthy, it inhibits
b
-glucosidase, glucoamylase, and isomaltase
hibitors of
these two compounds at C4 is non-essential for the inhibition of
almond -glucosidase. It is indicated that C4 is a good position to
modify isofagomine as a result to discover new -glycosidase
b-glycosidase. The configurational difference between
more strongly than 1-deoxynojirimycin (DNJ, Fig. 1).5 Interestingly,
isogalactofagomine, a diastereoisomer of isofagomine, also appears
b
to be extremely potent against
b
-glucosidase.6
b
In spite of considerable efforts have been expended to develop
iminosugars as potent glycosidase inhibitors, their lack of selectivity
has been shown to cause problems and side effects in therapeutic
applications.1a Modification of a known iminosugar inhibitor is
inhibitors. Secondly, the strong electron-withdrawing gem-
difluoromethylene group would greatly affect the pKa of imino-
sugars, which could have some interesting consequences, such as
increasing iminosugars selectivity toward a certain glycosidase.9
Consequently, we expected that the presence of a CF2 group at C4
of isofagomine analogues would change their biological activity
and selectivity and led us to further study their structure–activity
relationship.
* Corresponding author. Tel.: þ86 21 54925187; fax: þ86 21 64166128.
E-mail address: flq@mail.sioc.ac.cn (F.-L. Qing).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.02.079

3718
R.-j. Li et al. / Tetrahedron 65 (2009) 3717–3727
OH
OH
OH
OH
OH
HO
isogalactofagomine
NH
OH
N
R
HO
HO
HO
HO
HO
HO
NH
NH
OH
isofagomine
1-deoxynojirimycin (DNJ)
Zavesca R = Bu
Miglitol R = hydroxethyl
Figure 1. Selected glycosidase inhibitors.
OH
OH
OH
OH
F
HO
HO
F
NH
HO
NH
HO
NH
isofagomine
isogalactofagomine
F
R3
F
R5
N
R2
R4
R1
8: R1=OH, R2=H, R3=H, R4=CH2OH, R5=Bn
9: R1=H, R2=OH, R3=CH2OH, R4=H, R5=Bu
1: R1=H, R2=OH, R3=CH2OH, R4=H, R5=H
2: R1=OH, R2=H, R3=CH2OH, R4=H, R5=H
3: R1=H, R2=OH, R3=H, R4=CH2OH, R5=H 10: R1=OH, R2=H, R3=CH2OH, R4=H, R5=Bu
4: R1=OH, R2=H, R3=H, R4=CH2OH, R5=H
11: R1=H, R2=OH, R3=H, R4=CH2OH, R5=Bu
5: R1=H, R2=OH, R3=CH2OH, R4=H, R5=Bn 12: R1=OH, R2=H, R3=H, R4=CH2OH, R5=Bu
6: R1=OH, R2=H, R3=CH2OH, R4=H, R5=Bn 13: R1=H, R2=OH, R3=H, R4=CH2OH, R5=(CH2)2OH
7: R1=H, R2=OH, R3=H, R4=CH2OH, R5=Bn 14: R1=OH, R2=H, R3=H, R4=CH2OH, R5=(CH2)2OH
Figure 2. Rational design of 4-deoxy-4,4-difluoroisofagomine analogues 1–14.
2. Results and discussion
2.1. Chemistry
58% and 51% yields, respectively, over three steps by oxidation with
NaIO4 and subsequent reduction with NaBH4. The target molecules
4-deoxy-4,4-difluoroisofagomine analogues, (3R,5R)-4,4-difluoro-
5-(hydroxymethyl)piperidin-3-ol
1 and (3S,5R)-4,4-difluoro-5-
Our strategy to construct 4,4-difluoropiperidine ring was mainly
based on difluoromethylated building blocks 15 and 16 developed
in our group (Scheme 1).10 Compounds 15 and 16 were prepared
from 1-(R)-glyceraldehyde acetonide in 10 steps. Starting
from compound 15, a series of 4-deoxy-4,4-difluoroisofagomine
analogues 1, 2, 5, 6, 9, and 10 were synthesized. Since any
diastereoisomers of 4-deoxy-4,4-difluoroisofagomine is meaning-
ful to evaluate its bioactivity and further investigate the structure–
activity relationship, the racemic diastereoisomers of alcohol 17
were obtained in quantitative yield by reduction of compound 15
with NaBH4 in the presence of CeCl3$7H2O. Treatment of alcohol 17
with benzyl bromide in the presence of sodium hydride and cata-
lytic tetrabutylammonium iodide gave compound 18 in 98% yield.
The conversion of 18 to the key intermediate diols 19 and 20 was
achieved by the following two steps: (1) ozonation of alkene in
dichloromethane/methanol at ꢀ78 ꢁC and (2) reduction of resulting
dialdehyde with NaBH4. Gratifyingly, diastereoisomers 19 and 20
could be readily separated by column chromatography in 45% and
43% yields, respectively. Diols 19 and 20 were subjected to meth-
ylsulfonyl chloride, respectively, followed by cyclization of corre-
sponding mesylates with neat benzylamine to afford piperidines 21
and 22 in 52% and 84% yields, respectively.11 However, when
compounds 21 and 22 were treated with hydrogen in the presence
of 20% Pd(OH)2/C or less active 10% Pd/C in methanol at rt, all of the
four benzyl groups were removed. The selective deprotection of
three benzylethers was carried out by treatment of piperidines 21
and 22 with BCl3 in heptane/dichloromethane at 0 ꢁC.12 Finally, the
resulting alcohols were converted to target molecules 5 and 6 in
(hydroxymethyl)piperidin-3-ol 2 were obtained by hydrogenation
of 5 and 6 in the presence of 20% Pd(OH)2/C in methanol. The N-
butyl iminosugars 9 and 10 were obtained from the diols 19 and 20
by cyclization of corresponding mesylates with neat n-butylamine
in five steps using similar procedure.
Similarly, starting from compound 16, 4,4-difluroroisofagomine
analogues 3, 4, 7, 8, 11, and 12 were successfully synthesized
(Scheme 2). For the synthesis of N-hydroxyethyliminosugars 13 and
14, the intermediates 33 and 34 were protected with benzoyl
chloride, and the resulting benzoylates were converted to com-
pounds 37 and 38 using similar strategy as described for prepara-
tion of compound 1. Finally, treatment of 37 and 38 with NH3/
MeOH afforded the desired iminosugars 13 and 14.
The absolute configurations of target molecules 3–4, 7–8, and
11–14 were assigned by the X-ray crystal structure of compound 813
(Fig. 3) based on the known configuration at C5 that derived from
gem-difluoromethylated ketones 16.10 Since compounds 1, 2, 5, 6,
and 9, 10 are enantiomers of compounds 3, 4, 7, 8 and 11, 12, re-
spectively, we can easily confirm their absolute configurations by
comparison of optical rotations.
2.2. Enzymology
The synthesized 4-deoxy-4,4-difluoroisofagomine analogues
were evaluated to their inhibition activities toward eight glycosidases
namely the
yeast, and Bacillius stearothermophilus,
charomyces fragilis, Aspergillus orizae and bovine liver,
b
-glucosidase from almonds,
a
-glucosidase from baker
-galactosidases from Sac-
-galactosidase
b
a

R.-j. Li et al. / Tetrahedron 65 (2009) 3717–3727
3719
OBn
F
OBn
F
F
F
BnO
O
BnO
ref. 10
O
O
+
O
O
H
15
16
OBn
OBn
OBn
F
F
F
F
F
F
BnO
BnO
c
BnO
BnO
b
a
quant.
98%
OBn
HO
OH
O
18
15
17
OBn
F
OBn
F
F
F
F
F
F
F
R1
R2
R1
R2
R1
R2
R1
R2
BnO
f,g
d,e
h
HO
HO
N
N
N
OH
Bn
Bn
H
19: R1=H, R2=OBn, 45%
20: R1=OBn, R2=H, 43%
21: R1=H, R2=OBn, 52%
22: R1=OBn, R2=H, 84%
5: R1=H, R2=OH, 58% 1: R1=H, R2=OH, 88%
6: R1=OH, R2=H, 51% 2: R1=OH, R2=H, 80%
i,j
OBn
F
F
F
F
R1
R2
R1
R2
BnO
k,l
HO
N
N
9: R1=H, R2=OH, 40%
10: R1=OH, R2=H, 62%
23: R1=H, R2=OBn, 52%
24: R1=OBn, R2=H, 68%
Scheme 1. Synthesis of 4-deoxy-4,4-difluroroisofagomine analogues 1–14 from compounds 15 and 16. Reagents and conditions: (a) NaBH4, CeCl3$7H2O, MeOH; (b) NaH, BnBr, TBAI,
THF; (c) O3, CH2Cl2/MeOH (1:1), ꢀ78 ꢁC, then NaBH4, ꢀ78 ꢁC to rt; (d) MsCl, Et3N, DMAP, CH2Cl2; (e) BnNH2, 80 ꢁC; (f) i. BCl3 (1 M in heptane), CH2Cl2, 0 ꢁC; (g) NaIO4, H2O, MeOH,
then NaBH4; (h) 20% Pd(OH)2/C, H2, MeOH; (i) MsCl, Et3N, DMAP, CH2Cl2; (j) n-BuNH2, reflux; (k) BCl3 (1 M in heptane), CH2Cl2, 0 ꢁC; (l) NaIO4, H2O, MeOH, then NaBH4.
from Green Coffee beans,
a
-mannosidases from Jack beans. All assays
Comparisonof the Ki of compounds 1–4 versusb-glucosidasefrom
were performed at 25 ꢁC and pH 6.8 using the corresponding nitro-
phenyl glycoside substrates. The Ki values obtained are summarized
in Table 1.
almonds with literature values for isofagomine and some analogues
(39–46, Fig. 4)7f,14 shows that the introduction of the gem-difluoride
atC4hasaminorinfluenceoninhibition(Fig. 4).Compound1is10–15
times weaker than isofagomine 43 and isogalactofagomine 39, but is
two-fold stronger than the 4-deoxyisofagomine 46. This means there
is some positive contribution to binding from a hydroxyl group re-
gardless of configuration that cannot be emulated by the difluoride,
butthatthedifluorideneverthelessdoescontributetobindingsinceit
is better than deoxy.
It is also seen that compounds 2–4 are actually slightly more
potent than the hydroxylated analogues 40–45. This can be explained
by the wrong configuration of 40–45, which makes the removal of
wrongly positioned OH advantageous at least when replaced with
difluoride. Obviously the electron-withdrawing effect of gem-
difluoromethylene group (CF2) must be crucial for the binding as it
decreases the pKa of the amine in these compounds. By using NMR,15
we determined the pKa for 1 and 2 to 6.86 and 7.57, respectively.
Comparing these values with the pKa of hydroxylated isofagomines
39, 43, 40, and 44 that are 8.4, 8.8, 9.2 and 9.4,16,17 respectively, we see
that the difference is 1.5–1.9 pH units, which is substantial. This
means that at the test pH of 6.8, compounds 1 and 2 are not fully
protonated, while the other inhibitors are. In any case, the data show
that when modifying C4 the change in inhibition is not simply
a product of changing pKa: the pKa values of 1, 43, 39, and 46 are 6.86,
8.8, 8.4, and 9.0 while pKi values are 5.9, 7.0, 7.0, and 5.6, respectively.
The N-substituted compounds 5–14 showed insignificant in-
hibition of all eight enzymes at concentrations of 0.2 or 1 mM
depending on the solubility of the compounds, which meant that
Ki0s were above those values. This is in accordance with previous
results that have showed that alkylation of the amine in iso-
fagomine impedes inhibition.14 Likewise compounds 1–4 displayed
no or negligible inhibition (Ki>1 mM) against all the enzymes ex-
cept
liver. However toward those two enzymes the inhibition was
competitive and gave the Ki values 1.2, 4270, 980, and 950
versus -glucosidase and 165, 610, 2480 and 250 M versus
galactosidase (Table 1).
b-glucosidase from almond and b-galactosidase from bovine
mM
b
m
b-
It is known that the stereochemistry of an azasugar glycosidase
inhibitor is crucial for its ability to bind the enzyme, since many hy-
droxyl groups are involved in the binding, epimerisation of a single
hydroxyl group may change the inhibition level significantly.14 Ste-
reochemical resemblance with the substrate is likewise crucial.
Compound 1 resembles, through the stereochemistry at C3 and C5,
D
-glucose,
resembles
4, being enantiomers of 1 and 2, respectively, resemble the corre-
sponding -hexoses. In this light, the inhibition profile of compounds
1–4 is understandable: compound 1 is a good inhibitor of -gluco-
sidase and inhibits -galactosidase while the other inhibitors are
D
-mannose,
D
-galactose, and
D-talose, while compound 2
D
-gulose, -idose,
D
D-altrose or
D-allose. Compounds 3 and
L
b
The pH dependency of the inhibition of b-glucosidase by 1 was
b
determined and is shown in Chart 1. The data show a very sharp
curve with a maximum of inhibition located at pH 6.8, which is
identical to pKa. In contrast to the gem-4,4-difluoromethylated
weaker. The absence of a hydroxyl group at C2 is the explanation why
mannosidase inhibition is negligible (Table 1).

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R.-j. Li et al. / Tetrahedron 65 (2009) 3717–3727
OBn
F
OBn
OBn
F
F
F
F
F
BnO
BnO
BnO
BnO
b
c
a
quant.
98%
OBn
OH
O
16
25
26
OBn
F
OBn
F
F
F
F
F
F
F
R1
R2
R1
R2
R1
R2
OH
R1
R2
BnO
HO
HO
d,e
f,g
h
N
N
H
HO
N
Bn
Bn
7: R1=H, R2=OH, 77% 3: R1=H, R2=OH, 84%
8: R1=OH, R2=H, 47% 4: R1=OH, R2=H, 79%
27: R1=H, R2=OBn, 42%
28: R1=OBn, R2=H, 42%
29: R1=H, R2=OBn, 84%
30: R1=OBn, R2=H, 89%
k,l
i,j
OBn
F
OBn
F
F
F
F
F
R1
R2
m
R1
R2
BnO
R1
R2
BnO
HO
N
N
N
OH
31: R1=H, R2=OBn, 65%
32: R1=OBn, R2=H, 79%
11: R1=H, R2=OH, 58%
12: R1=OH, R2=H, 59%
33: R1=H, R2=OBn, 58%
34: R1=OBn, R2=H, 70%
o
OBn
F
F
F
F
F
F
R1
R2
R1
R2
BnO
R1
HO
p,q
r
HO
R2
N
N
N
OBz
OBz
OH
13: R1=H, R2=OH, 96%
14: R1=OH, R2=H, 90%
35: R1=H, R2=OBn, 99%
36: R1=OBn, R2=H, 96%
37: R1=H, R2=OH, 74%
38: R1=OH, R2=H, 75%
Scheme 2. Synthesis of 4,4-difluroroisofagomine analogues 3–4, 7–8, and 13–14 from compound 16. Reagents and conditions: (a) NaBH4, CeCl3$7H2O, MeOH, rt; (b) NaH, BnBr,
TBAI, THF; (c) i. O3, CH2Cl2/MeOH (1:1), ꢀ78 ꢁC; ii. NaBH4, ꢀ78 ꢁC to rt; (d) i. MsCl, Et3N, DMAP, CH2Cl2; ii. BnNH2, 80 ꢁC; (e) i. BCl3 (1 M) in heptane, CH2Cl2, 0 ꢁC; ii. NaIO4, H2O,
MeOH, rt; iii. NaBH4; (f) 20% Pd(OH)/C, H2, MeOH, rt; (g) i. MsCl, Et3N, DMAP, CH2Cl2; ii. H2NCH2CH2OH, 80 ꢁC; (h) i. MsCl, Et3N, DMAP, CH2Cl2; ii. n-BuNH2, reflux; (i) i. 20% Pd(OH)/
C, H2, MeOH; ii. NaIO4, H2O, MeOH, rt; iii. NaBH4; (j) BzCl, DMAP, Et3N, CH2Cl2; (k) i. 10% Pd/C, H2, MeOH; ii. NaIO4, H2O, MeOH, rt; iii. NaBH4; (l) NH3/MeOH.
nojirimicin derivatives that have the unprotonated form as the
most active inhibitor form,9 no such information can be extracted
here. Both unprotonated and protonated forms may be active. The
data are consistent either with protonated inhibitor binding to
monoprotonated enzyme (the active form) or protonated inhibitor
binding to unprotonated (inactive) enzyme.
From the pKa values the stereochemical substituent constant
of an axial fluorine in the
predicted, which is useful for empirical pKa predictions.16,17 From
the pKa of 1 and 2 we can calculate a constant of
g position of the ring atom can be
s
¼1.2, which is
a difference of 0.2 from the value of a fluorine atom in the
equatorial position.17
3. Conclusion
In summary, 4-deoxy-4,4-difluoroisofagomine analogues 1–14
were synthesized. The biological evaluation showed that (3R,5R)-
F
F
OH
HO
4,4-difluoro-5-(hydroxymethyl)piperidin-3-ol
1 was a good
N
inhibitor of -glucosidase from almonds, while alkylated or ste-
b
Bn
8
reoisomeric analogues were significantly weaker. This is however
similar to the behavior of isofagomine. The work shows that when
a hydroxyl group is unessential it can be replaced by the gem-
difluoro with minor change or even increase in the inhibition. The
pH dependence of enzyme activity and inhibition study shows
that the strong electron-withdrawing effect of gem-difluoro-
methylene group indeed decreases the pKa value of compound 1
significantly. There may be cases where such a modulation will be
advantageous.
Figure 3. The X-ray crystallographic structure of compound 8.

R.-j. Li et al. / Tetrahedron 65 (2009) 3717–3727
3721
Table 1
Inhibition constants at 25 ꢁC of 4,4-difluoroisofagomine analogues 1–14 at pH 6.8
Enzyme
Ki (mM)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
b
a
a
b
b
b
a
a
-Glucosidasea
-Glucosidaseb
-Glucosidasec
-Galactosidased
-Galactosidasee
-Galactosidasef
-Galactosidaseg
-Mannosidaseh
1.2
4270
980
950
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>200
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
NDi
ND
ND
ND
>1000
>1000
>1000
ND
ND
ND
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
>1000
ND
ND
ND
ND
>1000
>1000
165
>1000
>1000
>1000
>1000
>1000
>1000
610
>1000
>1000
>1000
>1000
>1000
>1000
2480
>1000
>1000
>1000
>1000
>1000
>1000
250
>1000
>1000
>1000
>1000
>1000
>1000
>200
>200
>200
>200
>200
>1000
>1000
>200
>200
>200
>200
>200
ND
ND
a
From almond.
b
From baker yeast.
From B. stearothermophilus.
From bovine liver.
From S. fragilis.
c
d
e
f
From A. oryzae.
g
h
i
From coffee beans.
From Jack beans.
Not determined.
4. Experimental section
4.1. General
The substrates used were 2-nitrophenyl-
4-nitrophenyl- -galactopyranoside, 4-nitrophenyl-
anoside, 4-nitrophenyl- -glucopyranoside, or 4-nitrophenyl-a-D-
b
-
D
-galactopyranoside,
a-
D
b-D-glucopyr-
a-
D
mannopyranoside. Also added was 0.02–0.1 mL of a solution of
either the inhibitor or water, and finally each cuvette was filled up
to a total volume of 1.9 mL with distilled water. Four of the samples
contained the inhibitor at a fixed concentration but with varying
concentrations of nitrophenyl glycoside. The other four samples
contained no inhibitor, but also varying concentrations of nitro-
phenyl glycoside. Finally the reaction was started by adding 0.1 mL
of a diluted solution of enzyme solution. The formation of 4- or 2-
nitrophenol was monitored for 2 min at 25 ꢁC by measurement of
the absorbance at 400 nm. Initial velocities were calculated from
the slopes from each reaction and used to construct two Hanes
plots ([S]/v vs [S]), one with and one without inhibitor, which also
was used to check whether inhibition was competitive. From the
two Michaelis–Menten constants, Km and Km0, thus obtained, the
inhibition constant, Ki, was calculated. All assays were performed at
25 ꢁC. The inhibition constants (Ki) were obtained from the formula
4.1.1. Chemistry
All reagents were used as received from commercial sources,
unless specified otherwise, or prepared as described in the litera-
ture. THF was distilled from sodium and benzophenone.
Dichloromethane was distilled from calcium hydride. Petroleum
ether refers to the fraction of light petroleum ether with bp 60–
90 ꢁC. 1H NMR and 13C NMR spectra were recorded on Bruker AM-
300, Bruker AM-400 or Varian Mercury-300 spectrometers. 19F
NMR was recorded on a Bruker AM-300 spectrometer (FCCl3 as
outside standard and low field is positive). Chemical shifts (d) are
reported in parts per million, and coupling constants (J) are in hertz.
Optical rotations were measured using a Perkin–Elmer 241 or 341
polarimeter. Crystallographic data were analyzed with Rigaku FCR
Diffractimer. All melting points are uncorrected.
0
4.1.2. Enzyme inhibition
Ki¼[I]/(KM0/KMꢀ1), where KM and KM are Michaelis–Menten con-
Each glycosidase assay was performed by preparing eight 2 mL
samples in cuvettes, containing 1 mL sodium phosphate buffer
(0.1 M) of right pH along with 0.04–0.80 mL of different substrates.
The concentration of the substrate was in the range of 0.25–5 Km.
stants with and without inhibitor present.
4.2. General procedure of the preparation of iminosugars
1, 2, 5, 6, and 9, 10
OH
F
F
4.2.1. (R,E)-6-((S)-1,2-Bis(benzyloxy)ethyl)-5,5-difluoroocta-2,7-
dien-4-ol (17)
A solution of 15 (1.00 g, 2.5 mmol) and CeCl3$7H2O (1.86 g,
5.00 mmol) in methanol (27 mL) was cooled to 0 ꢁC, and NaBH4
F
OH
F
F
F
F
NH
OH
HO
HO
NH
F
NH
HO
NH
OH
OH
2 K 4270
3 K 980
4 K 950
1 K 1.2
i
i
i
i
OH
OH
OH
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
OH
OH
OH
NH
OH
HO
HO
NH
NH
HO
NH
OH
OH
39 K 0.097
41 K >1000
i
40 K >1000
42 K >1000
i
i
i
OH
OH
OH
HO
HO
HO
HO
NH
HO
HO
NH
HO
NH
NH
43 K 0.1
OH
44 K >1000
0.1
0
46 K 2.8
45 K >1000
i
i
i
i
5
5.5
6
6.5
7
7.5
8
pH
Figure 4. Comparison of the inhibition constants of 4-deoxy-4,4-difluoroisofagomine
analogues 1–4 with their isofagomine analogues for -glucosidase from almonds. Data
for compounds 39–46 are taken from Refs. 7f and 14. Ki in M.
b
Chart 1. pH versus 1/Ki for 1 at 25 ꢁC versus
b
-glucosidase from almonds.
m

3722
R.-j. Li et al. / Tetrahedron 65 (2009) 3717–3727
(0.19 g, 5.00 mmol) was added in portions. The solution remained
at the temperature for 10 min and quenched with saturated
aqueous NH4Cl. The mixture was extracted with ethyl acetate, dried
over Na2SO4, and the solvent was removed under reduced pressure.
The residue was purified by silica gel chromatography (petroleum
ether/ethyl acetate¼15:1) to give compound 17 (1.00 g, 100%) as
d
7.40–7.24 (m, 15H), 4.72–4.53 (m, 6H), 4.16–4.11 (m, 1H), 4.03–
3.69 (m, 6H), 2.87–2.71 (m, 1H), 2.52 (br, 2H); 13C NMR (75.4 MHz,
CDCl3) 137.73, 137.35, 128.41, 128.33, 128.11, 127.96, 127.94, 127.83,
d
127.74, 127.66, 127.57, 123.92 (t, J¼250.1 Hz), 80.26 (t, J¼26.9 Hz),
76.20 (t, J¼3.7 Hz), 73.97, 73.43 (d, J¼6.8 Hz), 72.30, 69.97, 60.21 (t,
J¼4.2 Hz), 57.91 (t, 5.8 Hz), 46.09 (t, J¼20.6 Hz);19F NMR (282 MHz,
a colorless oil: 1H NMR (300 MHz, CDCl3)
d
7.27–7.38 (m, 10H),
CDCl3)
d
ꢀ107.894 (t, J¼13.5 Hz, 2F); IR (thin film) nmax 3431, 3032,
5.65–5.85 (m, 2H), 5.50–5.61 (m, 1H), 5.22–5.32 (m, 2H), 4.52–4.82
(m, 4H), 4.18–4.35 (m, 2H), 3.89–4.03 (m, 1H), 3.73–3.78 (m, 1H),
3.54–3.64 (m, 1H), 2.20 (br, 1H), 1.73–1.75 (d, 2H); 19F NMR
2876, 1497, 1455, 1099, 737, 698 cmꢀ1
; MS (ESI) m/z 487.3
[(MþH)þ], 509.3 [(MþNa)þ]; HRMS calcd for C28H32F2O5Na:
509.2101. Found: 509.21100.
(282 MHz, CDCl3) ꢀ110.54
d
(ddd, J¼252.9, 16.9, 10.4 Hz, 0.33F),
ꢀ113.86 (dt, J¼252.4, 17.8, 7.05 Hz, 0.33F), ꢀ109.28 (ddd, J¼253.2,
20.3, 6.5 Hz, 0.67F), ꢀ116.46 (ddd, J¼253.8, 16.9, 9.6 Hz, 0.67F); IR
4.2.4. (3R,5R)-1-Benzyl-3-(benzyloxy)-5-((S)-1,2-bis(benzyloxy)-
ethyl)-4,4-difluoropiperidine (21)
(thin film) nmax 3424, 3033, 2867, 1497, 1454, 1092, 737, 698 cmꢀ1
;
A solution of compound 19 (400 mg, 0.82 mmol) in dry
MS (ESI) m/z 425 [(MþNa)þ]. Anal. Calcd for C24H28F2O3: C, 71.62;
dichloromethane (12 mL) was cooled to 0 ꢁC. NEt3 (0.62 mL,
4.44 mmol), DMAP (17 mg, 0.14 mmol), and MsCl (0.3 mL,
3.94 mmol) were added. The reaction mixture was stirred at rt for
4 h and then quenched with water. The two layers were separated
and the aqueous layer was extracted with dichloromethane. The
combined organic layer was dried over Na2SO4 and concentrated.
The crude product was dissolved in BnNH2 (distilled before use,
1.2 mL) and heated for 18 h at 80 ꢁC. Then the mixture was directly
purified by silica gel column chromatography (petroleum ether/
H, 7.01. Found: C, 71.53; H, 6.91.
4.2.2. ((2S,3R,E)-4,4-Difluoro-3-vinyloct-6-ene-1,2,5-triyl)tris
(oxy)tris(methylene)tribenzene (18)
To a suspended solution of NaH (60% in oil, 186 mg, 4.47 mmol),
Bu4NI (83 mg, 0.22 mmol), and THF (10 mL) at 0 ꢁC under nitrogen
atmosphere, a solution of compound 17 (900 mg, 2.24 mmol) in
THF (8 mL) was added dropwise. The mixture was stirred at rt for
30 min. BnBr (768 mg, 4.47 mmol) in THF (2 mL) was added drop-
wise at 0 ꢁC. The reaction mixture was stirred at rt for 1.5 h and
then quenched with saturated aqueous NH4Cl (5 mL). The layers
were separated and the aqueous layer was extracted with Et2O
(15 mLꢂ3). The combined extracts was dried over Na2SO4 and
concentrated. The crude product was purified by silica gel column
chromatography (petroleum ether/ethyl acetate¼30:1) to give
compound 18 (1.08 g, 98%) as a colorless oil: 1H NMR (300 MHz,
ethyl acetate¼15:1) to give compound 21 (239 mg, 52% from
27
compound 19) as a clear oil: [
a
]
þ34.0 (c 1.0 CHCl3); 1H NMR
D
(300 MHz, CDCl3) d 4.90–4.51 (m, 6H), 4.15–4.11 (m, 1H), 3.84–3.70
(m, 2H), 3.65–3.53 (m, 3H), 3.03–2.99 (d, J¼10.8 Hz, 2H), 2.62–2.48
(m, 1H), 2.32–2.16 (m, 2H); 13C NMR (75.4 MHz, CDCl3)
d
138.27,
138.12, 137.60, 137.45, 128.78, 128.71, 128.41, 128.30, 128.27, 128.23,
128.19, 128.12, 127.76, 127.73, 127.48, 127.44, 127.20, 121.88 (t,
J¼250.7 Hz), 75.83 (t, J¼19.5 Hz), 74.72, 73.42 (dd, J¼13.2, 11.1 Hz),
73.17, 72.37, 70.75, 61.65, 50.31 (d, J¼7.9 Hz), 50.62 (d, J¼7.4 Hz),
CDCl3)
d 7.36–7.27 (m, 15H), 5.87–5.40 (m, 2H), 5.27–5.08 (m, 1H),
4.72–4.51 (m, 5H), 4.31–4.25 (m, 1H), 4.16–3.88 (m, 2H), 3.77–3.73
44.97 (t, J¼20.1 Hz); 19F NMR (282 MHz, CDCl3)
d
ꢀ110.83 (d,
(d, J¼10.5 Hz, 1H), 3.61–3.53 (m, 1H), 3.42–3.17 (m, 1H), 1.82–1.75
J¼240.8 Hz, 1F), ꢀ128.50 (d, J¼239.7 Hz, 1F); IR (thin film) nmax
3031, 2871, 1496, 1455, 1105, 1085, 737, 698 cmꢀ1; MS (ESI) m/z
558.4 [(MþH)þ], 580.4 [(MþNa)þ]; HRMS calcd for C35H38F2NO3:
558.2811. Found: 558.28143.
(m, 3H); 19F NMR (282 MHz, CDCl3)
d
ꢀ108.94 (dt, J¼256.6, 14.1 Hz,
0.57F), ꢀ113.03 (ddd, J¼255.5, 17.8, 8.5 Hz, 0.57F), ꢀ109.80 (ddd,
J¼255.2, 25.9, 4.2 Hz, 0.44F), ꢀ115.77 (ddd, J¼255.5, 18.9, 5.6 Hz,
0.44F); IR(thin film) nnmax 3066, 3032, 2865, 1498, 1455, 1207, 1099,
736, 697 cmꢀ1; MS (ESI) m/z 515.3 [(MþNa)þ]. Anal. Calcd for
C31H34F2O3: C, 75.59; H, 6.96. Found: C, 75.52; H, 6.94.
4.2.5. (3S,5R)-1-Benzyl-3-(benzyloxy)-5-((S)-1,2-
bis(benzyloxy)ethyl)-4,4-difluoropiperidine (22)
Using the same conditions as described for compound 21,
4.2.3. (2R,4R)-2-(Benzyloxy)-4-((S)-1,2-bis(benzyloxy)ethyl)-3,3-
difluoropentane-1,5-diol (19) and (2S,4R)-2-(benzyloxy)-4-((S)-
1,2-bis(benzyloxy)ethyl)-3,3-difluoropentane-1,5-diol (20)
compound 22 (481 mg, 84% for two steps) was prepared as a clear
27
oil from compound 20 (500 mg, 1.03 mmol): [
a]
þ18.6 (c 1.0,
D
CHCl3); 1H NMR (300 MHz, CDCl3)
d
7.50–7.32 (m, 20H), 4.83–4.65
A solution of compound 18 (1.05 g, 2.13 mmol) in methanol/
dichloromethane (25 mL, 1:1) was cooled to ꢀ78 ꢁC and treated
with ozone until the color of solution became blue. The cooling
bath was removed and NaBH4 (824 mg, 21.8 mmol) was added in
portions. The mixture was stirred for 1 h and then quenched with
saturated aqueous NH4Cl. The mixture was extracted with ethyl
acetate, dried over Na2SO4, and the solvent was removed under
reduced pressure. The crude product was purified by silica gel
column chromatography (petroleum ether/ethyl acetate¼2:1) to
(m, 4H), 4.61 (s, 2H), 4.16–4.11 (m, 1H), 3.92–3.51 (m, 6H), 3.11–2.94
(m, 3H), 2.42–2.36 (t, J¼10.5 Hz, 3H); 13C NMR (75.5 MHz, CDCl3)
d
138.34, 138.18, 137.66, 137.46, 128.95, 128.73, 128.22, 128.18,
128.13, 128.11, 128.07, 127.73, 127.58, 127.43, 127.37, 127.35, 127.12,
126.86, 121.95 (t, J¼246.9 Hz), 75.51, 75.44 (dd, J¼29.9, 21.3 Hz),
73.55, 73.13, 72.36 (d, J¼5.2 Hz), 71.15, 61.67, 53.32, 51.03, 41.64 (t,
J¼19.0 Hz); 19F NMR (282 MHz, CDCl3)
ꢀ112.08 (d, J¼247.0 Hz,1F),
d
ꢀ113.53 (dd, J¼245.3, 25.4 Hz, 1F); IR (thin film) nmax 3031, 2818,
1496, 1454, 1101, 736, 697 cmꢀ1; MS (ESI) m/z 558.4 [(MþH)þ];
HRMS calcd for C35H38F2NO3: 558.2818. Found: 558.28143.
give compounds 19 (445 mg, 43%) and 20 (466 mg, 45%) as clear oil.
28
Data of compound 19: [
a
]
þ3.1 (c 1.1, CHCl3); 1H NMR (300 MHz,
D
CDCl3)
d
7.41–7.36 (m, 15H), 4.76–4.55 (m, 6H), 4.12–4.08 (m, 1H),
4.2.6. (3R,5R)-1-Benzyl-4,4-difluoro-5-(hydroxymethyl)piperidin-
3-ol (5)
3.99–3.72 (m, 7H), 2.80–2.64 (m, 1H), 2.59 (s, 2H); 13C NMR
(75.4 MHz, CDCl3) 137.78, 137.72, 136.99, 128.53, 128.34, 128.16,
d
A solution of compound 21 (350 mg, 0.63 mmol) in dry
127.85, 127.74, 127.60, 123.76 (t, J¼250.3 Hz), 79.80 (t, J¼27.1 Hz),
75.86 (d, J¼5.4 Hz), 73.93, 73.41, 72.32, 70.37, 60.26, 58.05 (t,
J¼5.4 Hz), 46.84 (t, J¼20.0 Hz); 19F NMR (282 MHz, CDCl3)
dichloromethane (10 mL) was cooled to 0 ꢁC under nitrogen atmo-
sphere and BCl3 (1 M solution in heptane, 6.3 mL, 6.30 mmol) was
added. The reaction mixture remained at the temperature for 3 h and
then quenched with methanol (4 mL). The solvent was removed
under reduced pressure. The residue (203 mg) was dissolved in
methanol (35 mL) and the saturated aqueous NaIO4 (5.25 mL) was
added dropwise. The reaction mixture was stirred strongly for 15 min
and then cooled to 0 ꢁC. NaBH4 (343 mg, 9.10 mmol) was added in
d
ꢀ106.52 (ddd, J¼264.2, 22.8, 9.0 Hz, 1F), ꢀ107.54 (dt, J¼264.8,
13.8 Hz, 1F); IR (thin film) nmax 3422, 3032, 2877, 1497, 1455, 1104,
736, 698 cmꢀ1; MS (ESI) m/z 509.3 [(MþNa)þ]; HRMS calcd for
C28H32F2O5Na: 509.2118580. Found: 509.2110016. Data of com-
28
pound 20: [
a
]
ꢀ11.8 (c 1.1, CHCl3); 1H NMR(300 MHz, CDCl3)
D

R.-j. Li et al. / Tetrahedron 65 (2009) 3717–3727
3723
portions. The mixture was stirred for 30 min at rt and quenched with
4.2.10. (3R,5R)-3-(Benzyloxy)-5-((S)-1,2-bis(benzyloxy)ethyl)-1-
saturated aqueous NH4Cl. Methanol was removed under reduced
pressure. The resulting mixture was extracted with ethyl acetate. The
combined organic phase was dried over NaSO4 and concentrated. The
residue was purified by silica gel column chromatography (petro-
butyl-4,4-difluoropiperidine (23)
A
solution of compound 19 (200 mg, 0.41 mmol) in dry
dichloromethane (6 mL) was cooled to 0 ꢁC. NEt3 (0.31 mL,
2.22 mmol), DMAP (9 mg, 0.07 mmol), and MsCl (0.15 mL,
1.97 mmol) were added. The mixture was stirred at rt for 4 h and
then quenched with water. The two layers were separated and the
aqueous layer was extracted with dichloromethane. The combined
organic layer was dried over Na2SO4 and concentrated. The residue
was dissolved in n-BuNH2 (distilled before use, 4 mL) and refluxed
for 18 h. Then the mixture was directly purified by silica gel column
chromatography (petroleum ether/ethyl acetate¼20:1) to give
leum ether/ethyl acetate¼2:1) to give compound 5 (93 mg, 58% from
26
compound 21) as a white solid: mp 123–125 ꢁC; [
a]
D
þ26.7 (c 1.0,
MeOH); 1H NMR (300 MHz, MeOH-d4)
d 7.35–7.22 (m, 5H), 3.96–3.91
(dd, J¼11.1, 3.6 Hz, 1H), 3.89–3.75 (m, 1H), 3.65–3.49 (m, 3H), 3.11–
3.07 (m, 1H), 2.98–2.91 (m, 1H), 2.28–2.05 (m, 3H); 13C NMR
(75.4 MHz, CDCl3)
d 138.65, 130.35, 129.44, 128.53, 122.54 (t,
J¼246.3 Hz), 70.09 (t, J¼21.3 Hz), 62.87, 58.29 (d, J¼2.9 Hz), 57.25 (d,
J¼7.5 Hz), 54.28 (d, J¼8.1 Hz), 46.17 (t, J¼20.1 Hz); 19F NMR (282 MHz,
compound 23 (111 mg, 52% from compound 19) as a pale yellow oil:
27
MeOH-d4)
d
ꢀ117.47 (d, J¼222.2 Hz, 1F), ꢀ137.22 (d, J¼176.3 Hz, 1F);
[a
]
þ41.4 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3)
d 7.41–7.28 (m,
D
IR (KBr) nmax 3512, 2898, 1500, 1394, 1228, 1089, 760, 709 cmꢀ1; MS
(ESI) m/z 258.2 [(MþH)þ], 280.2 [(MþNa)þ]; HRMS calcd for
C13H18F2NO2: 258.13029. Found: 258.13001.
15H), 4.89–4.63 (m, 4H), 4.61–4.52 (dd, J¼15.3, 12.3 Hz, 2H), 4.10–
4.06 (m, 1H), 3.82–3.77 (dd, J¼10.8, 3 Hz, 2H), 3.76–3.63 (m, 1H),
3.59–3.53 (dd, J¼11.1, 6.9 Hz, 1H), 2.99–2.93 (m, 1H), 2.52–2.31 (m,
3H), 2.21–2.13 (td, J¼11.1, 1.5 Hz, 1H), 2.10–2.02 (t, J¼11.4 Hz, 1H),
1.45–1.35 (m, 2H), 1.32–1.23 (m, 2H), 0.93–0.89 (t, J¼6.9 Hz); 13C
4.2.7. (3S,5R)-1-Benzyl-4,4-difluoro-5-(hydroxymethyl)piperidin-
3-ol (6)
NMR (75.4 MHz, CDCl3)
d 138.32, 138.22, 137.71, 128.40, 128.30,
Using the same conditions as described for compound 5, com-
128.26, 127.87, 127.55, 127.54, 127.50, 121.95 (t, J¼250.7 Hz), 75.79
(t, J¼20.1 Hz), 74.77, 73.59 (d, J¼2.1 Hz), 73.30, 72.51, 71.03 (d,
J¼3.7 Hz), 57.26, 54.81 (d, J¼7.9 Hz), 50.65 (d, J¼7.4 Hz), 44.97 (t,
J¼19.5 Hz), 28.99, 20.50, 13.95; 19F NMR (282 MHz, CDCl3)
pound 6 (113 mg, 51% for there steps) was prepared as a white solid
27
from compound 22 (480 mg, 0.86 mmol): mp 113 ꢁC; [
a]
þ34.6 (c
D
1.0, MeOH); 1H NMR (300 MHz, MeOH-d4)
d 7.37–7.22 (m, 5H),
3.88–3.83 (dd, J¼10.5, 3.6 Hz, 1H), 3.78–3.69 (m, 1H), 3.61–3.54 (m,
3H), 2.93–2.90 (d, J¼10.2 Hz,1H), 2.76–2.72 (d, J¼11.1 Hz,1H), 2.52–
2.38 (m, 2H), 2.31–2.28 (m, 1H); 13C NMR (75.5 MHz, MeOH-d4)
d
ꢀ110.75 (d, J¼238.0 Hz, 1F), ꢀ128.43 (d, J¼232.9 Hz, 1F); IR (thin
film) nmax 3065, 3032, 2932, 2870, 1497, 1455, 1095, 735, 697 cmꢀ1
;
MS (ESI) m/z 524.5 [(MþH)þ], 546.5 [(MþNa)þ]; HRMS calcd for
d
137.35, 128.92, 127.97, 126.99, 121.38 (t, J¼247.8 Hz), 67.51 (t,
C32H39F2NO3Na: 546.28060. Found: 546.27902.
J¼25.9 Hz), 61.52, 57.76, 55.77, 52.41, 42.21 (t, J¼19.3 Hz); 19F NMR
(282 MHz, MeOH-d4)
d
ꢀ119.96 (d, J¼255.8 Hz, 1F), ꢀ123.86 (d,
4.2.11. (3S,5R)-3-(Benzyloxy)-5-((S)-1,2-bis(benzyloxy)ethyl)-1-
butyl-4,4-difluoropiperidine (24)
J¼249.9 Hz, 1F); IR (KBr) nmax 3290, 2839, 1473, 1168, 1085, 760,
703 cmꢀ1
;
MS (ESI) m/z 258.2 [(MþH)þ]; HRMS calcd for
Using the same conditions as described for compound 23,
C13H18F2NO2:258.13059. Found: 258.13001.
compound 24 (164 mg, 68%) was prepared as a clear oil from
24
compound 20 (225 mg, 0.46 mmol): [
a
]
D
þ18.5 (c 1.3, CHCl3); 1H
4.2.8. (3R,5R)-4,4-Difluoro-5-(hydroxymethyl)piperidin-3-ol (1)
A solution of compound 5 (60 mg, 0.23 mmol) in methanol
(5.2 mL) was hydrogenated in the presence of 20% Pd(OH)2/C
(30 mg) at atmospheric pressure and at rt. After stirring for 3 h, the
reaction mixture was filtrated and the solvent was evaporated. The
residue was purified by silica gel column chromatography
(dichloromethane/methanol¼5:1) to give compound 1 (35 mg,
NMR (300 MHz, CDCl3) d 7.48–7.30 (m, 15H), 4.90–4.86 (d,
J¼12.9 Hz, 1H), 4.75 (s, 2H), 4.73–4.69 (d, J¼12.6 Hz, 1H), 4.62 (s,
2H), 4.13–4.09 (dd, J¼6.9, 3.6 Hz, 1H), 3.88–3.84 (dd, J¼10.5, 2.4 Hz,
1H), 3.70–3.60 (m, 2H), 3.04–2.92 (m, 3H), 2.51–2.18 (m, 4H), 1.56–
1.51 (m, 2H), 1.48–1.31 (m, 2H), 1.01–0.96 (t, J¼7.2 Hz); 13C NMR
(75.4 MHz, CDCl3)
d 138.31, 128.19, 137.60, 128.25, 128.15, 128.08,
127.85, 127.75, 127.67, 127.41, 122.05 (dd, J¼254.4, 247.5 Hz), 75.40,
73.99 (dd, J¼29.9, 21.9 Hz), 73.17, 72.65, 72.40, 71.26, 57.42, 54.22 (d,
J¼5.7 Hz), 50.96 (d, J¼5.8 Hz), 41.39 (t, J¼19.0 Hz), 28.62, 20.53,
88%) as a white solid: mp 130–132 ꢁC; [
NMR (300 MHz, MeOH-d4)
a]
24 30.6 (c 0.7, MeOH); 1H
D
3.94–3.89 (dd, J¼11.4, 4.2 Hz, 1H),
d
3.76–3.62 (m, 1H), 3.59–3.53 (dd, J¼11.4, 8.7 Hz, 1H), 3.20–3.14 (dt,
J¼13.2, 3.6 Hz, 1H), 3.09–3.02 (m, 1H), 2.67–2.52 (m, 2H), 2.14–1.95
13.89; 19F NMR (282 MHz, CDCl3)
d
ꢀ112.53 (d, J¼243.1 Hz),
ꢀ113.42 (dd, J¼243.9, 27.4 Hz); IR (thin film) nmax 3032, 2932, 2872,
2816, 1497, 1455, 1096, 736, 697 cmꢀ1; MS (ESI) m/z 524.5
[(MþH)þ]; HRMS calcd for C32H40F2NO3: 524.29703. Found:
524.29708.
(m, 1H); 13C NMR (75.5 MHz, MeOH-d4)
d
122.68 (t, J¼247.3 Hz),
70.56 (t, J¼21.1 Hz), 58.40 (t, J¼4.7 Hz), 50.32 (d, J¼5.6 Hz), 47.74 (t,
J¼19.5 Hz), 46.92 (d, J¼6.1 Hz); 19F NMR (282 MHz, MeOH-d4)
d
ꢀ112.45 (d, J¼237.2 Hz, 1F), ꢀ132.94 (br, 1F); IR (KBr) nmax 3431,
3265, 2941, 1461, 1217, 1107 cmꢀ1; MS (ESI) m/z 168.1 [(MþH)þ];
4.2.12. (3R,5R)-1-Butyl-4,4-difluoro-5-(hydroxymethyl)piperidin-
3-ol (9)
HRMS calcd for C6H12F2NO2: 168.08295. Found: 168.08306.
A solution of compound 23 (174 mg, 0.33 mmol) in methanol/
ethyl acetate (7:1, 8 mL) was hydrogenated in the presence of 10% Pd/
C (116 mg) at atmospheric pressure and at rt. After stirring for 3 days,
the reaction mixture was filtrated and concentrated. The residue was
dissolved in methanol (19 mL) and the saturated aqueous NaIO4
(2.1 mL) was added dropwise. The reaction mixture was stirred
strongly for 15 min. NaBH4 (158 mg, 4.18 mmol) was added in por-
tions. The reaction mixture was stirred for 30 min at rt and then
quenched with saturated aqueous NH4Cl. Methanol was removed as
possiblyunder reduced pressure. Theresultingmixturewasextracted
withethyl acetate. The combined organicphasewasdried overNaSO4
andconcentrated. Thecrudeproductwaspurifiedbysilicagelcolumn
4.2.9. (3S,5R)-4,4-Difluoro-5-(hydroxymethyl)piperidin-3-ol (2)
Using the same conditions as described for compound 1, com-
pound 2 (40 mg, 80%) was prepared as a white solid from com-
20
pound 22 (78 mg, 0.3 mmol): mp 120 ꢁC; [
a
]
þ65.5 (c 0.5, MeOH);
D
1H NMR (300 MHz, MeOH-d4)
d
3.93–3.88 (dd, J¼11.1, 3.9 Hz, 1H),
3.73–3.66 (m, 1H), 3.56–3.49 (dd, J¼11.4, 8.1 Hz, 1H), 3.22–3.17 (m,
1H), 3.01–2.97 (d, J¼14.4 Hz, 1H), 2.89–2.83 (dt, J¼13.8, 1.8 Hz, 1H),
2.58–2.50 (t, J¼10.8 Hz,1H), 2.48–2.29 (m,1H); 13C NMR (75.4 MHz,
MeOH-d4)
d
123.09 (t, J¼242.9 Hz), 68.09 (dd, J¼31.6, 21.9 Hz),
58.71 (t, J¼4.0 Hz), 50.37 (d, J¼5.2 Hz), 46.70 (d, J¼6.3 Hz), 43.46 (t,
J¼18.4 Hz); 19F NMR (282 MHz, MeOH-d4)
ꢀ112.23 (d, J¼241.4 Hz,
d
1F), ꢀ121.33 (d, J¼242.8 Hz, 1F); IR (KBr) nmax 3292, 2935, 2745,
1459, 1158, 1076 cmꢀ1; MS (ESI) m/z 168.1 [(MþH)þ]; HRMS calcd
for C6H12F2NO2: 168.0832. Found: 168.08306.
chromatography to give compound 9 (30 mg, 40% forthree steps from
25
compound 23) as a clear oil: [
a
]
þ9.4 (c 0.5, CHCl3); 1H NMR
D
(300 MHz,CDCl3)
d
4.02–3.82(m, 3H),2.79–2.62(m,4H), 2.43–2.38(t,

3724
R.-j. Li et al. / Tetrahedron 65 (2009) 3717–3727
J¼7.2 Hz, 2H), 2.25–2.15 (m,1H),1.54–1.43 (m, 2H),1.39–1.25 (m, 2H),
2H), 2.61 (br, 1H), 2.55–2.43 (t, J¼17.7 Hz, 1H); 13C NMR (75.4 MHz,
0.95–0.90 (t, J¼7.5 Hz, 3H); 19F NMR (282 MHz, CDCl3)
d
ꢀ104.88 (br,
120.99 (t,
CDCl3) d 137.74, 137.61, 137.32, 128.47, 128.39, 128.36, 128.00, 127.97,
1F), ꢀ117.00 (br, 1F); 13C NMR (100 MHz, CDCl3)
d
127.88, 127.81, 127.75, 127.60, 124.01 (t, J¼249.8 Hz), 79.85 (t,
J¼25.0 Hz), 75.59 (t, J¼3.2 Hz), 74.07, 73.27, 73.09, 70.86, 60.47 (t,
J¼4.5 Hz), 57.86 (t, J¼5.2 Hz), 45.68 (t, J¼20.4 Hz); 19F NMR
J¼244.8 Hz), 68.29 (dd, J¼27.6, 20.5 Hz), 60.75, 57.25, 57.12, 54.00,
43.00 (t, J¼19.8 Hz), 28.82, 20.41,13.86; IR (thin film) nmax 3354, 2960,
2874, 1473, 1221, 1100 cmꢀ1; MS (ESI) m/z 224.2 [(MþH)þ]; HRMS
calcd for C10H20O2NF2: 224.1473. Found: 224.14566.
(282 MHz, CDCl3)
d
ꢀ105.25 (ddd, J¼263.4, 18.0, 12.7 Hz, 1F),
ꢀ108.68 (ddd, J¼263.4, 16.1, 9.9 Hz, 1F); IR (thin film) nmax 3425,
3033, 2934, 2873, 1498, 1455, 1115, 1029, 739, 698 cmꢀ1; MS (ESI)
4.2.13. (3S,5R)-1-Butyl-4,4-difluoro-5-(hydroxymethyl)piperidin-
3-ol (10)
m/z 509.3 [(MþNa)þ]; HRMS calcd for C28H32F2O5Na: 509.21315.
25
Found: 509.21100. Compound 28: [
a]
ꢀ3.6 (c 0.9, CHCl3); 1H NMR
D
Using the same conditions as described for compound 9, com-
(300 MHz, CDCl3) d 7.36–7.32 (m, 15H), 4.79–4.50 (m, 6H), 4.26–
pound 10 (39 mg, 62% for three steps) was prepared as a pale yel-
4.22 (td, J¼5.4, 1.8 Hz, 1H), 3.99–3.81 (m, 5H), 3.63–3.61 (d,
25
low oil from compound 24 (145 mg, 0.28 mmol): [
a
]
þ26.1 (c 0.4,
J¼6.0 Hz, 2H), 2.56–2.44 (m, 1H), 2.24 (br, 2H); 13C NMR (75.4 MHz,
D
CHCl3); 1H NMR (300 MHz, CDCl3)
d
3.97–3.92 (dd, J¼11.1, 3.3 Hz,
CDCl3) d 137.80, 137.64, 137.08, 128.50, 128.36, 128.35, 128.09,
2H), 3.75–3.69 (dd, J¼10.8, 4.8 Hz, 1H), 3.43 (br, 2H), 2.90–2.88 (d,
J¼6.0 Hz, 1H), 2.65 (s, 2H), 2.48–2.34 (m, 4H), 1.51–1.41 (m, 2H),
1.36–1.24 (m, 2H), 0.92–0.88 (t, J¼7.2 Hz, 3H); 13C NMR (75.5 MHz,
127.98,127.84,127.77,127.70,127.55,123.71 (t, J¼250.1 Hz), 79.26 (t,
J¼27.4 Hz), 75.43 (t, J¼2.7 Hz), 73.56, 73.29 (d, J¼0.8 Hz), 73.21,
71.11, 60.21 (t, J¼4.1 Hz), 58.05 (dd, J¼2.7, 7.6 Hz), 45.78 (t,
CDCl3)
d
121.63 (t, J¼248.6 Hz), 67.79 (t, J¼25.4 Hz), 59.93, 57.00,
J¼21.1 Hz); 19F NMR (282 MHz, CDCl3)
d
ꢀ105.97 (ddd, J¼263.1,
56.21, 53.46, 41.65 (t, J¼19.9 Hz), 28.87, 20.45, 13.89; 19F NMR
16.6, 9.0 Hz, 1F), ꢀ109.13 (ddd, J¼264.5, 26.2, 5.4 Hz, 1F); IR (thin
(282 MHz, CDCl3)
d
ꢀ114.23 (br, 1F), ꢀ120.52 (br, 1F); IR (thin film)
film) nmax 3439, 3033, 2871, 1498, 1455, 1207, 1116, 738, 699 cmꢀ1
;
nmax 3253, 2954, 2899, 1459, 1115, 1080 cmꢀ1; MS (ESI) m/z 224.2
[(MþH)þ]; HRMS calcd for C10H20O2NF2: 224.1473. Found:
224.14566.
MS (ESI) m/z 509.3 [(MþNa)þ]; HRMS calcd for C28H32F2O5Na:
509.2121. Found: 509.21100.
4.3.4. (3R,5S)-1-Benzyl-3-(benzyloxy)-5-((S)-1,2-
bis(benzyloxy)ethyl)-4,4-difluoropiperidine (29)
4.3. General procedure of the preparation of iminosugars 3, 4,
7, 8, 11, 12, and 13, 14
Using the same conditions as described for compound 21,
compound 29 (481 mg, 84% for two steps) was prepared as a pale
29
4.3.1. (S,E)-6-((S)-1,2-Bis(benzyloxy)ethyl)-5,5-difluoroocta-2,7-
dien-4-ol (25)
yellow oil from compound 27 (500 mg, 1.03 mmol): [
a
]
ꢀ17.3 (c
D
1.0, CHCl3); 1H NMR (300 MHz, CDCl3)
d
7.40–7.30 (m, 20H), 4.76–
Using the same conditions as described for compound 17,
compound 25 (610 mg, quant.) was prepared as a clear oil from
compound 16 (610 mg, 1.52 mmol): 1H NMR (300 MHz, CDCl3)
4.54 (m, 6H), 4.12–4.07 (dd, J¼10.1, 4.5 Hz, 1H), 3.78–3.49 (m, 5H),
3.14–3.10 (d, J¼11.4 Hz, 1H), 2.99–2.94 (d, J¼12.9 Hz, 1H), 2.90–2.76
(m, 1H), 2.53–2.45 (t, J¼10.8 Hz, 1H), 2.36–2.31 (m, 1H); 13C NMR
d
7.27–7.38 (m, 10H), 5.77–6.01 (m, 2H), 5.51–5.68 (m, 1H), 5.11–
(75.5 MHz, CDCl3) d 138.49, 138.23, 137.79, 129.03, 128.28, 128.20,
5.34 (m, 2H), 4.65–4.75 (dd, J¼11.4, 21.3 Hz, 2H), 4.45–4.57 (dd,
J¼12, 20.7 Hz, 2H), 4.11–4.32 (m, 2H), 3.43–3.65 (m, 2H), 2.93–3.20
(m, 1H), 2.24 (br, 1H), 1.74–1.77 (m, 3H); 19F NMR (282 MHz, CDCl3)
127.77, 127.61, 127.54, 127.47, 127.43, 127.17, 121.93 (t, J¼247.3 Hz),
74.83, 74.49 (d, J¼10.4 Hz), 74.21, 73.25, 72.25, 71.94, 61.74, 53.11,
51.25, 40.83 (t, J¼18.4 Hz); 19F NMR (282 MHz, CDCl3)
ꢀ111.67 (d,
d
d
ꢀ111.38 (ddd, J¼249.9, 11.8, 16.1 Hz, 0.5F), ꢀ113.74 (dt, J¼250.4,
J¼244.2 Hz), ꢀ115.97 (dd, J¼243.4, 24.5 Hz); IR (thin film) nmax
3031, 2919, 2864, 2265, 1687, 1496, 1455, 1103, 736, 697 cmꢀ1; MS
(ESI) m/z 558.3 [(MþH)þ]; HRMS calcd for C35H38F2NO3: 558.2815.
Found: 558.28143.
14.7 Hz, 0.5F), ꢀ111.59 (ddd, J¼252.4, 25.1, 2.82 Hz, 0.5F), ꢀ117.06
(ddd, J¼252.7, 21.2, 7.1 Hz, 0.5F); IR (thin film) nmax 3424, 3033,
2918, 2866, 1498,1454,1205,1093, 736, 698 cmꢀ1; MS (ESI) m/z 420
[(MþNH4)þ]. Anal. Calcd for C24H28F2O3: C, 71.62; H, 7.01. Found: C,
71.74; H, 7.01.
4.3.5. (3S,5S)-1-Benzyl-3-(benzyloxy)-5-((S)-1,2-
bis(benzyloxy)ethyl)-4,4-difluoropiperidine (30)
4.3.2. ((2S,3S,E)-4,4-Difluoro-3-vinyloct-6-ene-1,2,5-triyl)tris
(oxy)tris(methylene)tribenzene (26)
Using the same conditions as described for compound 21,
compound 30 (50 mg, 89% for two steps) was prepared as a pale
26
Using the same conditions as described for compound 18,
compound 26 (3.85 g, 98%) was prepared as a clear oil from com-
yellow oil from compound 28 (50 mg, 0.1 mmol): [
a
]
ꢀ25.4 (c 1.0,
D
CHCl3); 1H NMR (300 MHz, CDCl3)
d
7.46–7.37 (m, 20H), 4.96–4.61
pound 25 (3.2 g, 1.52 mmol): 1H NMR (300 MHz, CDCl3)
d
7.38–7.27
(m, 6H), 4.23–4.18 (dd, J¼9.6, 4.8 Hz, 1H), 3.91–3.67 (m, 5H), 3.20–
(m, 15H), 6.00–5.69 (m, 2H), 5.63–5.46 (m, 1H), 5.30–4.28 (m, 6H),
4.26–4.06 (dt, J¼46.2, 6.6 Hz, 1H), 4.01–3.88 (m, 1H), 3.59–3.53 (m,
1H), 3.47–3.42 (m, 1H), 3.32–2.95 (m, 1H), 1.86–1.79 (m, 3H); 19F
3.10 (m, 2H), 2.61–2.39 (m, 3H); 13C NMR (75.4 MHz, CDCl3)
d
138.10, 138.12, 137.60, 128.73, 128.67, 128.22, 128.19, 128.12,
128.07, 127.80, 127.66, 127.60, 127.44, 127.08, 126.60, 121.93 (t,
J¼250.3 Hz), 75.83 (t, J¼19.6 Hz), 73.78, 73.24, 73.05, 70.83, 61.69,
56.75, 54.29 (d, J¼7.46 Hz), 51.16 (d, J¼8.0 Hz), 43.66 (t, J¼19.5 Hz);
NMR (282 MHz, CDCl3)
d
ꢀ110.77 (m, 1F), ꢀ112.00 (dd, J¼254.9,
28.5 Hz, 0.5F), ꢀ115.68 (ddd, J¼253.2, 20.6, 2.3 Hz, 0.5F); IR (thin
film) nmax 3032, 2867, 1498, 1454, 1207, 1101, 736, 697 cmꢀ1; MS
(ESI) m/z 515.3 [(MþNa)þ]. Anal. Calcd for C31H34F2O3: C, 75.59; H,
6.96. Found: C, 75.34; H, 7.14.
19F NMR (282 MHz, CDCl3)
(d, J¼212.6 Hz, 1F); IR (thin film) nmax 3035, 2926, 2872, 1674, 1498,
1456, 1201, 1136, 738, 699 cmꢀ1; MS (ESI) m/z 558.3 [(MþH)þ];
HRMS calcd for C35H38F2NO3: 558.2815. Found: 558.28143.
d
ꢀ108.96 (d, J¼230.4 Hz, 1F), ꢀ129.97
4.3.3. (2R,4S)-2-(Benzyloxy)-4-((S)-1,2-bis(benzyloxy)ethyl)-3,3-
difluoropentane-1,5-diol (27) and (2S,4S)-2-(benzyloxy)-4-((S)-
1,2-bis(benzyloxy)ethyl)-3,3-difluoropentane-1,5-diol (28)
4.3.6. (3R,5S)-1-Benzyl-4,4-difluoro-5-(hydroxymethyl)piperidin-
3-ol (7)
Using the same conditions as described for compounds 19 and
20, compounds 27 (330 mg, 42%) and 28 (315 mg, 40%) were pre-
Using the same conditions as described for compound 5, com-
pound 7 (78 mg, 77% for three steps) was prepared as a white solid
29
pared as clear oils from compound 26 (790 mg, 1.6 mmol). Com-
from compound 29 (242 mg, 0.43 mmol): mp 114 ꢁC; [
a]
ꢀ35.2 (c
D
27
pound 27: [
d
a]
þ5.3 (c 0.7, CHCl3); 1H NMR(300 MHz, CDCl3)
1.0, MeOH); 1H NMR (300 MHz, CDCl3)
d 7.30–7.19 (m, 5H), 3.87–
D
7.38–7.28 (m, 15H), 4.78–4.49 (m, 6H), 4.26–4.22 (t, J¼5.4 Hz, 1H),
3.82 (dd, J¼11.4, 3.9 Hz, 2H), 3.69–3.64 (dd, J¼11.4, 5.1 Hz, 1H),
3.99–3.97 (d, 2H), 3.93–3.76 (m, 3H), 3.68–3.59 (dd, J¼10.8, 16.2 Hz,
3.58–3.46 (dd, J¼23.1, 13.2 Hz, 2H), 2.99–2.83 (m, 3H), 2.61 (s, 2H),

R.-j. Li et al. / Tetrahedron 65 (2009) 3717–3727
3725
2.34 (s, 2H); 13C NMR (75.4 MHz, CDCl3)
d
138.65, 129.01, 128.57,
128.16, 127.90, 127.76, 127.72, 127.50, 127.43, 127.42, 122.16 (t,
J¼247.2 Hz), 74.08, 73.96 (dd, J¼32.0, 20.4 Hz), 73.23 (2C), 72.56 (d,
J¼2.2 Hz), 72.03, 57.59, 54.24 (d, J¼6.5 Hz), 51.16 (d, J¼7.5 Hz), 40.66
(t, J¼19.3 Hz), 28.86 (d, J¼8.1 Hz), 20.58 (d, J¼8.1 Hz), 13.99; 19F
127.69, 121.52 (t, J¼248.7 Hz), 67.73 (t, J¼25.4 Hz), 61.70, 59.82,
55.77, 53.07, 41.60 (t, J¼18.9 Hz); 19F NMR (282 MHz, CDCl3)
d
ꢀ114.30 (br, 1F), ꢀ119.27 (br, 1F); IR (KBr) nmax 3286, 2962, 2840,
1499, 1473, 1168, 1085, 760, 703 cmꢀ1
;
MS (ESI) m/z 258.2
NMR (282 MHz, CDCl3)
d
ꢀ111.58 (d, J¼244.5 Hz), ꢀ115.41 (dd,
[(MþH)þ]; HRMS calcd for C13H18F2NO2: 258.1301. Found:
J¼243.6, 31.6 Hz); IR (thin film) nmax 3032, 2957, 2932, 2867, 1498,
1455, 1117, 736, 697 cmꢀ1; MS (ESI) m/z 524.4 [(MþH)þ]; HRMS
calcd for C32H40F2NO3: 524.2976. Found: 524.29708.
258.13001.
4.3.7. (3S,5S)-1-Benzyl-4,4-difluoro-5-(hydroxymethyl)piperidin-
3-ol (8)
4.3.11. (3S,5S)-3-(Benzyloxy)-5-((S)-1,2-bis(benzyloxy)ethyl)-1-
butyl-4,4-difluoropiperidine (32)
Using the same conditions as described for compound 5, com-
pound 8 (97 mg, 47% for three steps) was prepared as a white solid
Using the same conditions as described for compound 23,
29
from compound 30 (518 mg, 0.93 mmol): mp 123 ꢁC; [
a
]
ꢀ27.1 (c
compound 32 (171 mg, 79% for two steps) was prepared as a pale
D
28
0.5, MeOH); 1H NMR (300 MHz, MeOH-d4)
d
7.34–7.23 (m, 5H),
yellow oil from compound 28 (200 mg, 0.41 mmol): [
a]
ꢀ28.5 (c
D
3.95–3.90 (dd, J¼11.1, 3.3 Hz, 1H), 3.88–3.74 (m, 1H), 3.65–3.55 (dd,
J¼16.8, 12.9 Hz, 2H), 3.55–3.48 (dd, J¼11.1, 8.4 Hz, 1H), 3.10–3.07 (d,
J¼7.8 Hz, 1H), 2.96–2.92 (m, 1H), 2.27–2.05 (m, 3H); 13C NMR
0.9, CHCl3); 1H NMR (300 MHz, CDCl3)
d 7.40–7.19 (m, 15H), 4.90–
4.53 (m, 6H), 4.12–4.07 (dd, J¼9.9, 5.4 Hz, 1H), 3.79–3.58 (m, 3H),
3.04–3.01 (m, 2H), 2.41–2.20 (m, 5H), 1.47–1.36 (m, 2H), 1.34–1.24
(m, 2H), 0.95–0.90 (t, J¼7.2 Hz, 3H); 13C NMR (75.4 MHz, CDCl3)
(75.4 MHz, MeOH-d4)
d 138.69, 130.33, 129.40, 128.49, 122.50 (t,
J¼247.5 Hz), 70.11 (t, J¼20.7 Hz), 62.88 (d, J¼1.1 Hz), 58.27 (d,
d 138.26, 138.09, 137.73, 128.38, 128.31, 128.25, 127.96, 127.83,
J¼3.5 Hz), 57.28 (d, J¼7.5 Hz), 54.28 (d, J¼8.1 Hz), 46.21 (t,
127.57, 127.55, 122.07 (t, J¼249.0 Hz), 75.82 (t, J¼20.1 Hz), 73.78,
73.52 (d, J¼2.1 Hz), 73.29 (d, J¼1.6 Hz), 73.23, 71.17, 57.34, 54.87 (d,
J¼7.9 Hz), 51.11 (d, J¼8.4 Hz), 43.67 (t, J¼20.1 Hz), 29.09, 20.50,
J¼19.6 Hz); 19F NMR (282 MHz, MeOH-d4)
ꢀ117.78 (d, J¼272.4 Hz,
d
1F), ꢀ137.52 (d, J¼197.4 Hz, 1F); IR (KBr) nmax 3512, 2929, 2898,
2843, 1500, 1394, 1228, 1201, 760, 709 cmꢀ1; MS (ESI) m/z 258.2
[(MþH)þ]; HRMS calcd for C13H18F2NO2: 258.1301. Found:
258.13001.
13.96; 19F NMR (282 MHz, CDCl3)
ꢀ130.66 (d, J¼223.3 Hz); IR (thin film) nmax 3032, 2957, 2932, 2863,
1497, 1455, 1121, 736, 697 cmꢀ1; MS (ESI) m/z 524.5 [(MþH)þ];
HRMS calcd for C32H40F2NO3: 524.2974. Found: 524.29708.
d
ꢀ109.81 (d, J¼237.7 Hz),
4.3.8. (3R,5S)-4,4-Difluoro-5-(hydroxymethyl)piperidin-3-ol (3)
Using the same conditions as described for compound 1, com-
pound 3 (26 mg, 84%) was prepared as a white solid from com-
4.3.12. (3R,5S)-1-Butyl-4,4-difluoro-5-(hydroxymethyl)piperidin-
3-ol (11)
Using the similar conditions as described for compound 9,
compound 11 (32 mg, 58% for three steps) was prepared as a clear
20
pound 7 (48 mg, 0.19 mmol): mp 104 ꢁC; [
a]
ꢀ66.4 (c 0.5, MeOH);
D
1H NMR (300 MHz, MeOH-d4)
d
3.92–3.87 (dd, J¼11.1, 3.9 Hz, 1H),
27
3.70–3.65 (m, 1H), 3.55–3.49 (dd, J¼11.1, 8.4 Hz, 1H), 3.20–3.16 (m,
1H), 2.99–2.81 (dd, J¼39.3, 14.4 Hz, 2H), 2.55–2.48 (t, J¼10.2 Hz,
oil from compound 31 (129 mg, 0.25 mmol): [
a
]
D
ꢀ21.9 (c 1.0,
CHCl3); 1H NMR (300 MHz, CDCl3)
d
3.98–3.93 (dd, J¼11.1, 3.6 Hz,
1H), 2.45–2.27 (m, 1H); 13C NMR (75.4 MHz, MeOH-d4)
d
123.07
2H), 3.75–3.69 (dd, J¼10.8, 4.5 Hz, 1H), 3.18 (br, 3H), 2.90–2.88 (m,
(dd, J¼251.5, 243.5 Hz), 68.15 (dd, J¼31.6, 21.3 Hz), 58.72 (t,
2H), 2.53 (s, 2H), 2.47–2.34 (m, 4H), 1.51–1.41 (m, 2H), 1.36–1.24 (m,
J¼4.6 Hz), 50.42 (d, J¼5.1 Hz), 46.76 (d, J¼6.3 Hz), 43.60 (t,
2H), 0.93–0.88 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 121.57
J¼19.5 Hz); 19F NMR (282 MHz, MeOH-d4)
d
ꢀ112.79 (d, J¼241.4 Hz,
(t, J¼248.6 Hz), 67.71 (t, J¼25.3 Hz), 59.89, 56.98, 56.12, 53.40, 41.54
1F), ꢀ122.13 (d, J¼240.3 Hz,1F); IR (KBr) nmax 3314, 2941,1457,1364,
1157, 1072 cmꢀ1; MS (ESI) m/z 168.1 [(MþH)þ]; HRMS calcd for
C6H12F2NO2: 168.0836. Found: 168.08306.
(t, J¼20.6 Hz), 28.79, 20.41, 13.87; 19F NMR (282 MHz, CDCl3)
d
ꢀ110.03 (br, 1F), ꢀ115.99 (br, 1F); IR (thin film) nmax 3365, 2961,
2875, 1173, 1111, 1081 cmꢀ1; MS (ESI) m/z 224.2 [(MþH)þ]; HRMS
calcd for C10H20O2NF2: 224.14533. Found: 224.14566.
4.3.9. (3S,5S)-4,4-Difluoro-5-(hydroxymethyl)piperidin-3-ol (4)
Using the same conditions as described for compound 1, com-
pound 4 (36 mg, 79%) was prepared as a white solid from com-
4.3.13. (3S,5S)-1-Butyl-4,4-difluoro-5-(hydroxymethyl)piperidin-
3-ol (12)
27
pound 8 (70 mg, 0.27 mmol): mp 138 ꢁC; [
a
]
D
ꢀ29.0 (c 1.0, MeOH);
Using the similar conditions as described for compound 9,
1H NMR (300 MHz, MeOH-d4)
d
3.94–3.89 (dd, J¼11.1, 3.3 Hz, 1H),
compound 12 (38 mg, 59% for three steps) was prepared as a pale
25
3.75–3.62 (m, 1H), 3.59–3.53 (dd, J¼11.4, 8.7 Hz, 1H), 3.20–3.13 (dt,
yellow oil from compound 32 (152 mg, 0.29 mmol): [
a
]
ꢀ9.9 (c
D
J¼13.2, 3.3 Hz, 1H), 3.09–3.02 (dt, J¼12.9, 4.2 Hz, 1H), 2.67–2.52 (m,
1.3, CHCl3); 1H NMR (300 MHz, CDCl3)
d
4.12–3.80 (m, 5H), 2.82–
2H), 2.14–1.95 (m, 1H); 13C NMR (75.4 MHz, MeOH-d4)
d
122.67 (t,
2.69 (m, 3H), 2.42–2.37 (t, J¼7.2 Hz, 2H), 2.26–2.12 (m, 1H), 1.53–
J¼246.9 Hz), 70.57 (t, J¼21.3 Hz), 58.421 (t, J¼4.7 Hz), 50.34 (d,
1.43 (m, 2H),1.38–1.24 (m, 2H), 0.94–0.89 (t, J¼7.2 Hz, 3H); 13C NMR
J¼5.4 Hz), 47.75 (t, J¼19.2 Hz), 46.92 (d, J¼6.3 Hz); 19F NMR
(100 MHz, CDCl3)
d
120.90 (t, J¼249.1 Hz), 68.31 (t, J¼20.5 Hz),
(282 MHz, MeOH-d4)
d
ꢀ113.98 (d, J¼244.5 Hz, 1F), ꢀ134.58 (br,
60.95, 57.31, 57.17, 54.10, 42.81 (d, J¼19.3 Hz), 28.83, 20.42, 13.88;
1F); IR (KBr) nmax 3435, 3269, 2941, 1462, 1374, 1217 cmꢀ1; MS (ESI)
m/z 168.1 [(MþH)þ]; HRMS calcd for C6H12F2NO2: 168.0838. Found:
168.08306.
19F NMR (282 MHz, CDCl3)
d
ꢀ104.96 (br, 1F), ꢀ117.75 (br, 1F); IR
(thin film) nmax 3391, 3284, 2961, 2811, 1456, 1100 cmꢀ1; MS (ESI)
m/z 224.2 [(MþH)þ]; HRMS calcd for C10H20O2NF2: 224.1473.
Found: 224.14566.
4.3.10. (3R,5S)-3-(Benzyloxy)-5-((S)-1,2-bis(benzyloxy)ethyl)-1-
butyl-4,4-difluoropiperidine (31)
4.3.14. 2-((3R,5S)-3-(Benzyloxy)-5-((S)-1,2-bis(benzyloxy)ethyl)-
4,4-difluoropiperidin-1-yl)ethanol (33)
Using the same conditions as described for compound 23,
compound 31 (139 mg, 65% for two steps) was prepared as a pale
Using the same conditions as described for compound 21,
28
yellow oil from compound 27 (200 mg, 0.41 mmol): [
a
]
ꢀ4.8 (c
compound 33 (159 mg, 58% for two steps) was prepared as a yellow
D
27
1.1, CHCl3); 1H NMR (300 MHz, CDCl3)
d
7.42–7.31 (m, 15H), 4.85–
oil from compound 27 (262 mg, 0.54 mmol): [
a]
ꢀ13.5 (c 0.9,
D
4.59 (m, 6H), 4.13–4.08 (dd, J¼10.2, 4.5 Hz, 1H), 3.73–3.58 (m, 3H),
3.07–2.95 (q, J¼11.7 Hz, 2H), 2.85–2.67 (m, 1H), 2.49–2.27 (m, 4H),
1.54–1.43 (m, 2H),1.40–1.28 (m, 2H), 0.97–0.92 (t, J¼7.2 Hz, 3H); 13C
CHCl3); 1H NMR (300 MHz, CDCl3)
d 7.37–7.28 (m, 15H), 4.80–4.53
(m, 6H), 4.09–4.04 (dd, J¼10.2, 5.1 Hz, 1H), 3.70–3.61 (m, 3H), 3.59–
3.56 (t, J¼5.4 Hz, 2H), 3.02–2.95 (m, 2H), 2.82–2.46 (m, 6H); 13C
NMR (75.4 MHz, CDCl3)
d
138.48, 138.16, 137.70, 128.30, 128.24,
NMR (75.4 MHz, CDCl3) d 138.25, 138.02, 137.57, 128.41, 128.34,

3726
R.-j. Li et al. / Tetrahedron 65 (2009) 3717–3727
128.25, 127.84, 127.69, 127.58, 121.85 (t, J¼253.9 Hz), 74.52 (dd,
J¼29.7, 20.4 Hz), 73.92, 73.24, 73.21, 72.79, 71.28, 58.01, 57.88, 53.80
(d, J¼6.9 Hz), 50.53 (d, J¼6.9 Hz), 40.67 (t, J¼19.0 Hz); 19F NMR
J¼249.6 Hz), 76.38, 75.44 (t, J¼19.8 Hz), 73.29, 73.03, 72.78, 70.56,
61.97, 55.24, 54.42 (d, J¼8.0 Hz), 51.13 (d, J¼8.6 Hz), 43.42 (t,
J¼19.2 Hz); 19F NMR (282 MHz, CDCl3)
d
ꢀ109.56 (d, J¼228.9 Hz),
(282 MHz, CDCl3)
d
ꢀ111.03 (d, J¼245.3 Hz, 1F), ꢀ115.29 (dd,
ꢀ130.0 (d, J¼227.9 Hz); IR (thin film) nmax 3032, 2863, 1719, 1602,
1497, 1454, 1274, 1114, 739, 713, 698 cmꢀ1; MS (ESI) m/z 616.5
[(MþH)þ], 638.4 [(MþNa)þ]; HRMS calcd for C37H40O5NF2:
616.2870. Found: 616.28691.
J¼244.5, 26.2 Hz, 1F); IR (thin film) nmax 3032, 2868, 1497, 1455,
1102, 739, 698 cmꢀ1
;
MS (ESI) m/z 512.4 [(MþH)þ], 534.4
[(MþNa)þ]; HRMS calcd for C30H36F2NO4: 512.2615. Found:
512.26069.
4.3.18. 2-((3R,5S)-4,4-Difluoro-3-hydroxy-5-(hydroxymethyl)-
piperidin-1-yl)ethyl benzoate (37)
4.3.15. 2-((3S,5S)-3-(Benzyloxy)-5-((S)-1,2-bis(benzyloxy)ethyl)-
4,4-difluoropiperidin-1-yl)ethanol (34)
Pd/C (10%, 140 mg) was added to a solution of compound 35
(184 mg, 0.30 mmol) in methanol (10 mL). The reaction mixture
was stirred for 4 days under hydrogen atmosphere and then fil-
tered. The filtrate was concentrated. The residue was dissolved in
methanol (18 mL) and saturated aqueous NaIO4 was added drop-
wise. The reaction mixture was stirred strongly for 5 min at rt and
then cooled to 0 ꢁC. NaBH4 (143 mg, 3.78 mmol) was added in
portions and the mixture was stirred at the same temperature for
20 min followed by being quenched with saturated aqueous NH4Cl
(6 mL). Methanol was removed under reduced pressure and the
resulting mixture was extracted with ethyl acetate. The extracts
were combined and dried over Na2SO4. The solvent was removed.
The residue was purified by silica gel column chromatography
Using the same conditions as described for compound 21,
compound 34 (212 mg, 70% for two steps) was prepared as a yellow
26
oil from compound 28 (290 mg, 0.6 mmol): [
a
]
ꢀ36.6 (c 0.8,
D
CHCl3); 1H NMR (300 MHz, CDCl3)
d
7.39–7.28 (m, 15H), 4.89–4.52
(m, 6H), 4.11–4.06 (dd, J¼9.3, 5.1 Hz, 1H), 3.76–3.55 (m, 5H), 3.04–
3.01 (m, 2H), 2.57 (t, J¼5.7 Hz, 2H), 2.41 (m, 4H); 13C NMR
(75.4 MHz, CDCl3)
d 138.14, 138.00, 137.58, 128.48, 128.41, 128.32,
127.99, 127.85, 127.69, 127.66, 121.88 (t, J¼250.2 Hz), 75.70 (t,
J¼19.5 Hz), 73.63 (d, J¼2.1 Hz), 73.56, 73.27, 73.23 (d, J¼1.6 Hz),
70.74 (d, J¼2.1 Hz), 58.51 (d, J¼1.1 Hz), 58.08, 54.68 (d, J¼7.9 Hz),
51.03 (d, J¼8.4 Hz), 43.67 (t, J¼19.0 Hz); 19F NMR (282 MHz, CDCl3)
d
ꢀ109.89 (d, J¼241.1 Hz, 1F), ꢀ130.34 (d, J¼237.4 Hz, 1F); IR (thin
film) nmax 3032, 2931, 2868, 1497, 1455, 1116, 738, 698 cmꢀ1; MS
(ESI) m/z 512.4 [(MþH)þ], 534.5 [(MþNa)þ]; HRMS calcd for
C30H36F2NO4: 512.2585. Found: 512.26069.
(petroleum ether/ethyl acetate¼1:1) to give compound 37 (70 mg,
25
74% for two steps) as a white solid: mp 119–121 ꢁC; [
a]
ꢀ21.4 (c
D
0.4, CHCl3); 1H NMR (300 MHz, MeOH-d4)
d
8.04–8.02 (d, J¼7.5 Hz,
2H), 7.62–7.57 (t, J¼7.2 Hz, 1H), 7.49–7.44 (t, J¼8.1 Hz, 2H), 4.50–
4.41 (m, 2H), 3.89–3.84 (dd, J¼11.1 Hz, 3 Hz, 1H), 3.80–3.72 (m, 1H),
3.61–3.55 (dd, J¼10.5, 8.4 Hz,1H), 3.04–3.02 (d, J¼6.9 Hz,1H), 2.93–
2.79 (m, 3H), 2.72–2.68 (d, J¼12.3 Hz, 1H), 2.54–2.45 (m, 2H); 13C
4.3.16. 2-((3R,5S)-3-(Benzyloxy)-5-((S)-1,2-bis(benzyloxy)ethyl)-
4,4-difluoropiperidin-1-yl)ethyl benzoate (35)
DMAP (44 mg, 0.36 mmol), NEt3 (0.42 mL, 3.00 mmol), and BzCl
(distilled before use, 0.07 mL, 0.60 mmol) were added to a solution
of compound 33 (154 mg, 0.30 mmol) in dichloromethane (5.2 mL)
at 0 ꢁC under nitrogen atmosphere. The reaction mixture was stir-
red for 3 h at rt and quenched with saturated aqueous NH4Cl
(2 mL). The two layers were separated and the aqueous layers were
extracted with dichloromethane. The combined organic layer was
dried over Na2SO4 and concentrated. The crude product was puri-
NMR (75.4 MHz, MeOH-d4)
d 167.99, 134.28, 131.35, 130.57, 129.59,
122.62 (t, J¼248.0 Hz), 68.84 (t, J¼24.8 Hz), 63.64, 59.06, 57.65,
56.75, 54.18, 43.65 (t, J¼20.1 Hz); 19F NMR (282 MHz, MeOH-d4)
d
ꢀ116.51 (d, J¼243.1 Hz, 1F), ꢀ120.28 (d, J¼225.0 Hz, 1F); IR (KBr)
nmax 3269, 2838, 1716, 1602, 1453, 1279, 1072, 1020, 714 cmꢀ1; MS
(ESI) m/z 316.2 [(MþH)þ], 338.2 [(MþNa)þ]; HRMS calcd for
C15H20O4NF2: 316.1352. Found: 316.13415.
fied by silica gel column chromatography (petroleum ether/ethyl
26
acetate¼10:1) give compound 35 (184 mg, 99%) as a clear oil: [
a
]
4.3.19. 2-((3S,5S)-4,4-Difluoro-3-hydroxy-5-(hydroxymethyl)-
piperidin-1-yl)ethyl benzoate (38)
Using the same conditions as described for compound 37,
compound 38 (103 mg, 75% for two steps) was prepared as a white
solid from compound 36 (270 mg, 0.44 mmol): mp 77–79 ꢁC; [
D
ꢀ2.7 (c 0.3, CHCl3); 1H NMR (300 MHz, CDCl3)
d 8.09–8.06 (dd,
J¼7.2 Hz, 5.4H, 2H), 7.60–7.54 (td, J¼8.4, 1.5 Hz, 1H), 7.45–7.29 (m,
17H), 4.86–4.65 (m, 4H), 4.60 (s, 2H), 4.53–4.49 (t, J¼6 Hz, 2H),
4.16–4.11 (m, 3H), 3.21–3.09 (m, 2H), 3.00–2.75 (m, 3H), 2.67–2.59
25
a]
D
(t, J¼11.4 Hz, 2H); 13C NMR (75.4 MHz, CDCl3)
d
166.18, 138.36,
ꢀ16.0 (c 0.4, CHCl3); 1H NMR (300 MHz, CDCl3)
d 8.01–7.99 (d,
138.05, 137.52, 132.79, 129.93, 129.41, 128.25, 128.21, 128.17, 128.10,
127.70, 127.64, 127.62, 127.42, 127.38, 127.36, 121.72 (dd, J¼246.3,
254.9 Hz), 76.58, 74.06 (dd, J¼31.5, 20.3 Hz), 73.83, 73.10 (d,
J¼5.9 Hz), 72.48, 71.65, 62.45, 55.61, 54.25 (d, J¼6.9 Hz), 51.10 (d,
J¼7.5 Hz), 40.52 (t, J¼19.15 Hz); 19F NMR (282 MHz, CDCl3)
J¼7.2 Hz, 2H), 7.56–7.51 (t, J¼7.5 Hz, 1H), 7.44–7.38 (t, J¼15.3 Hz,
2H), 4.49–4.34 (m, 2H), 3.96–3.90 (dd, J¼11.4, 4.2 Hz,1H), 3.88–3.78
(m, 1H), 3.75–3.69 (dd, J¼11.4, 6.3 Hz, 1H), 2.93–2.72 (m, 4H), 2.60
(s, 2H), 2.21–2.15 (m, 1H); 13C NMR (75.4 MHz, CDCl3)
d 166.71,
133.15, 129.60, 129.50, 128.38, 120.88 (t, J¼249.6 Hz), 68.43 (t,
d
ꢀ111.02 (d, J¼245.1 Hz, 1F), ꢀ115.18 (dd, J¼245.6, 30.7 Hz, 1F); IR
J¼21.2 Hz), 61.74, 59.47, 56.99, 55.60, 53.23, 43.69 (t, J¼20.6 Hz); 19F
(thin film) nmax 3032, 2866, 1719, 1454, 1274, 1115, 738, 713,
698 cmꢀ1; MS (ESI) m/z 616.4 [(MþH)þ], 638.4 [(MþNa)þ]; HRMS
calcd for C37H40O5NF2: 616.2859. Found: 616.28691.
NMR (282 MHz, CDCl3)
d
ꢀ110.52 (br, 1F), ꢀ128.32 (br, 1F); IR (KBr)
nmax 3404, 3210, 2793, 1729, 1605, 1455, 1277, 1101, 708, 693 cmꢀ1
;
MS (ESI) m/z 316.2 [(MþH)þ], 338.2 [(MþNa)þ]; HRMS calcd for
C15H20O4NF2: 316.1335. Found: 316.13549.
4.3.17. 2-((3S,5S)-3-(Benzyloxy)-5-((S)-1,2-bis(benzyloxy)ethyl)-
4,4-difluoropiperidin-1-yl)ethyl benzoate (36)
4.3.20. (3R,5S)-4,4-Difluoro-1-(2-hydroxyethyl)-5-
Using the same conditions as described for compound 35,
(hydroxymethyl)piperidin-3-ol (13)
compound 36 (295 mg, 96%) was prepared as a pale yellow oil from
Compound 37 (89 mg, 0.28 mmol) was dissolved in a saturated
solution of ammonia in methanol (30 mL). The reaction solution
was stirred 32.5 h at rt and then concentrated. The residue was
purified by silica gel column chromatography (dichloromethane/
26
compound 34 (254 mg, 0.5 mmol): [
NMR (300 MHz, CDCl3)
a
]
ꢀ20.4 (c 0.5, CHCl3); 1H
D
d
8.16–8.13 (dd, J¼8.1, 1.2 Hz, 2H), 7.64–7.59
(t, J¼7.8 Hz, 1H), 7.50–7.35 (m, 15H), 4.95–4.90 (d, J¼12.3 Hz, 1H),
4.78–4.59 (m, 5H), 4.51–4.47 (t, J¼6 Hz, 2H), 4.22–4.17 (q, J¼9.9,
4.8 Hz, 1H), 3.84–3.66 (m, 3H), 3.22–3.18 (d, J¼10.2 Hz, 2H), 2.90–
2.86 (t, J¼5.7 Hz, 2H), 2.63–2.38 (m, 3H); 13C NMR (75.4 MHz,
methanol¼7:1) to give compound 13 (57 mg, 96%) as a clear oil:
25
[a
]
ꢀ37.9 (c 0.4, MeOH); 1H NMR (300 MHz, MeOH-d4)
d 3.91–
D
3.86 (dd, J¼11.1, 3.9 Hz, 1H), 3.78–3.66 (m, 1H), 3.65–3.61 (t,
J¼5.1 Hz, 2H), 3.58–3.52 (dd, J¼11.1, 9.3 Hz, 1H), 3.05–3.02 (d,
J¼10.2 Hz, 1H), 2.92–2.88 (d, J¼12 Hz, 1H), 2.63–2.38 (m, 4H), 2.24–
CDCl3) d 165.85, 137.92, 137.74, 137.35, 132.55, 129.67, 129.14, 127.99,
127.94, 127.88, 127.49, 127.45, 127.38, 127.18, 127.17, 121.48 (t,

R.-j. Li et al. / Tetrahedron 65 (2009) 3717–3727
3727
2.17 (t, J¼10.8 Hz, 1H); 13C NMR (100 MHz, MeOH-d4)
d 123.01 (t,
Whalen, L. J.; Greenberg, W. A.; Wong, C. H. J. Am. Chem. Soc. 2007, 129, 14811; (i)
Reddy, B. G.; Vankar, Y. D. Angew. Chem., Int. Ed. 2005, 44, 2001; (j) Zhu, X.;
Sheth, K. A.; Li, S.; Chang, H. H.; Fan, J. Q. Angew. Chem., Int. Ed. 2005, 44, 7450;
(k) Wu, C. Y.; Chang, C. F.; Chen, J. S. Y.; Wong, C. H.; Lin, C. H. Angew. Chem.,
Int. Ed. 2003, 42, 4661.
J¼245.7 Hz), 69.24 (t, J¼27.8 Hz), 60.63, 60.02, 59.13, 58.02 (t,
J¼2.8 Hz), 54.49, 43.42 (t, J¼17.4 Hz); 19F NMR (282 MHz, MeOH-d4)
d
ꢀ116.68 (d, J¼242.5 Hz, 1F), ꢀ121.60 (d, J¼243.9 Hz, 1F); IR (thin
film) nmax 3366, 2951, 2831, 1169, 1085, 1029 cmꢀ1; MS (ESI) m/z
212.1 [(MþH)þ], 234.1 [(MþNa)þ]; HRMS calcd for C8H15O3NF2Na:
234.0926. Found: 234.09122.
2. (a) Asano, N.; Nash, R. J.; Molyneux, R. J.; Fleet, G. W. J. Tetrahedron: Asymmetry
2000, 11, 1645; (b) Alper, J. Science 2001, 291, 2338.
3. (a) Butters, T. D.; Dwek, R. A.; Platt, F. M. Curr. Top. Med. Chem. 2003, 3, 561; (b)
Lieberman, R. L.; Wustman, B. A.; Huertas, P.; Powe, A. C.; Pine, C. W.; Khanna,
R.; Schlossmacher, M. G.; Ringe, D.; Petsko, G. A. Nat. Chem. Biol. 2007, 3, 101; (c)
Steet, R. A.; Chung, S.; Wustman, B.; Powe, A.; Do, H.; Kornfeld, S. A. Proc. Natl.
Acad. Sci. U.S.A. 2006, 103, 13813.
4. Jespersen, T. M.; Dong, W.; Sierks, M. R.; Skrydstrup, T.; Lundt, I.; Bols, M.
Angew. Chem., Int. Ed. Engl. 1994, 33, 1778.
5. Dong, W.; Jespersen, T.; Bols, M.; Skrydstrup, T.; Sierks, M. R. Biochemistry 1996,
35, 2788.
4.3.21. (3S,5S)-4,4-difluoro-1-(2-hydroxyethyl)-5-
(hydroxymethyl)piperidin-3-ol (14)
Using the same conditions as described for compound 13,
compound 14 (56 mg, 90%) was prepared as a clear oil from com-
25
pound 38 (92 mg, 0.29 mmol): [
(300 MHz, MeOH-d4)
a]
ꢀ28.4 (c 1.4, MeOH); 1H NMR
6. Ouchi, H.; Mihara, Y.; Watanabe, H.; Takahata, H. Tetrahedron Lett. 2004, 45,
7053.
D
d
3.95–3.77 (m, 2H), 3.69–3.65 (t, J¼5.7 Hz,
7. For modification of iminosugars by protection of hydroxyl groups, see: (a) Van
den Broek, L. A. G. M.; Vermaas, D. J.; Van Kemenade, F. J.; Tan, M. C. C. A.;
Rotteveel, F. T. M.; Zandberg, P.; Butters, T. D.; Miedema, F.; Ploegh, H. L.; Van
Boeckel, C. A. A. Recl. Trav. Chim. Pays-Bas 1994, 113, 507; For substitution of
hydroxyl groups with other functional groups, see: (b) Kajimoto, T.; Liu, K. K. C.;
Pederson, R. L.; Zhong, Z.; Ichikawa, Y.; Porco, J. A.; Wong, C. H. J. Am. Chem. Soc.
1991, 113, 6187; (c) Andersen, S. M.; Ebner, M.; Ekhart, C. W.; Gradnig, G.; Legler,
G. Carbohydr. Res. 1997, 301, 155; (d) Kieß, F. M.; Poggendorf, P.; Picasso, S.; Ja¨ger,
V. Chem. Commun. 1998, 119; (e) Popowycz, F.; Gerber-Lemaire, S.; Schu¨etz, C.;
Vogel, P. Helv. Chim. Acta 2004, 87, 800; For changing the stereoconfiguration,
see: (f) Asano, N.; Ikeda, K.; Yu, L.; Kato, A.; Takebayashi, K.; Adach, I.; Kato, I.;
Ouchi, H.; Takahata, H.; Fleet, G. W. J. Tetrahedron: Asymmetry 2005, 16, 223; (g)
Ichikawa, Y.; Igarashi, Y.; Ichikawa, M.; Suhara, Y. J. Am. Chem. Soc. 1998, 120,
3007; For alterations of the sugar ring size, see: (h) Shih, T. L.; Yang, R. Y.; Li, S. T.;
Chiang, C. F.; Lin, C. H. J. Org. Chem. 2007, 72, 4258; (i) Ribes, C.; Falomir, E.; Carda,
M.; Marco, J. A. Org. Lett. 2007, 9, 77; (j) Moriarty, R. M.; Mitan, C. I.; Branza-
Nichita, N.; Phares, K. R.; Parrish, D. Org. Lett. 2006, 8, 3465.
2H), 3.58–3.51 (dd, J¼10.5, 7.8 Hz, 1H), 3.11–2.99 (m, 2H), 2.62–2.59
(t, J¼5.4 Hz, 2H), 2.31–2.15 (m, 3H); 13C NMR (100 MHz, MeOH-d4)
d
122.72 (t, J¼245.6 Hz), 70.15 (t, J¼21.1 Hz), 60.48, 60.28, 58.60 (d,
J¼3.9 Hz), 58.08 (d, J¼7.1 Hz), 54.91 (d, J¼7.4 Hz), 46.34 (t,
J¼19.6 Hz); 19F NMR (282 MHz, MeOH-d4)
ꢀ116.53 (d, J¼241.7 Hz,
d
1F), ꢀ136.15 (br, 1F); IR (thin film) nmax 3363, 2946, 2836, 1473,
1220, 1096 cmꢀ1; MS (ESI) m/z 212.1 [(MþH)þ], 234.1 [(MþNa)þ];
HRMS calcd for C8H15O3NF2Na: 234.0928. Found: 234.09122.
Acknowledgements
The financial support of our research in this area by National
Natural Science Foundation of China and Shanghai Municipal Sci-
entific Committee was greatly acknowledged.
8. For the synthesis of gem-difluoroglycosides as glycosidases inhibitors, see:
Zhang, R.; McCarter, J. D.; Braun, C.; Yeung, W.; Brayer, G. D.; Withers, S. G.
J. Org. Chem. 2008, 73, 3070.
9. Wang, R. W.; Qiu, X. L.; Bols, M.; Ortega-Caballero, F.; Qing, F. L. J. Med. Chem.
2006, 49, 2989.
References and notes
10. Yang, Y. Y.; Xu, J.; You, Z. W.; Xu, X. H.; Qiu, X. L.; Qing, F. L. Org. Lett. 2007, 9,
5437.
11. Meyer, M. D.; DeBernardis, J. F.; Hancock, A. A. J. Med. Chem. 1994, 37, 105.
12. Tedesco, R.; Fiaschi, R.; Napolitano, E. J. Org. Chem. 1995, 60, 5316.
13. Crystal data have been deposited at the Cambridge Crystallographic Data
Center with reference number: CCDC 693075.
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